Islet β-cells are responsible for secreting all circulating insulin in response to rising plasma glucose concentrations. These cells are a phenotypically diverse population that express great functional heterogeneity. In mice, certain β-cells (termed ‘hubs’) have been shown to be crucial for dictating the islet response to high glucose, with inhibition of these hub cells abolishing the coordinated Ca²⁺ oscillations necessary for driving insulin secretion. These β-cell hubs were found to be highly metabolic and susceptible to pro-inflammatory and glucolipotoxic insults. In this study, we explored the importance of hub cells in human by constructing mathematical models of Ca²⁺ activity in human islets. Our simulations revealed that hubs dictate the coordinated Ca²⁺ response in both mouse and human islets; silencing a small proportion of hubs abolished whole-islet Ca²⁺ activity. We also observed that if hubs are assumed to be preferentially gap junction coupled, then the simulations better adhere to the available experimental data. Our simulations of 16 size-matched mouse and human islet architectures revealed that there are species differences in the role of hubs; Ca²⁺ activity in human islets was more vulnerable to hub inhibition than mouse islets. These simulation results not only substantiate the existence of β-cell hubs, but also suggest that hubs may be favorably coupled in the electrical and metabolic network of the islet, and that targeted destruction of these cells would greatly impair human islet function.

胰岛 β 细胞负责分泌所有循环胰岛素，以响应血浆葡萄糖浓度的升高。这些细胞是表型多样化的群体，表现出巨大的功能异质性。在小鼠中，某些 β 细胞（称为“中枢”）已被证明对于决定胰岛对高葡萄糖的反应至关重要，抑制这些中枢细胞会消除驱动胰岛素分泌所需的协调 Ca 2+^振荡。这些β细胞中枢被发现具有高度代谢性，并且容易受到促炎和糖脂毒性损伤。^{在本研究中，我们通过构建人类胰岛中 Ca 2+}活性的数学模型来探讨中枢细胞在人类中的重要性。我们的模拟表明，中枢决定了小鼠和人类胰岛中协调的 Ca ^2+反应；沉默一小部分中枢会消除整个胰岛的 Ca ²⁺活性。我们还观察到，如果假设集线器优先间隙连接耦合，则模拟可以更好地遵循可用的实验数据。我们对 16 个大小匹配的小鼠和人类胰岛结构进行的模拟表明，中枢的作用存在物种差异。人类胰岛中的Ca ²⁺活性比小鼠胰岛更容易受到中枢抑制的影响。这些模拟结果不仅证实了β细胞中枢的存在，而且表明中枢可能在胰岛的电和代谢网络中有利地耦合，并且有针对性地破坏这些细胞将极大地损害人类胰岛功能。